The genetic basis of IgE responsiveness leading to the expression of atopic diseases remains elusive. This is due, in part, to the multi-genetic nature of the disease involving a complex array of molecular genetic networks and environmental factors. Recent consistent evidence has suggested that chromosome 5q, 11q and 12q regions contain susceptibility gene(s) regulating IgE responsiveness and/or asthma. The overall objective of our continuing effort is, therefore, to determine the nature of the susceptibility gene(s) and its functional relevance. In this new grant application, we will target specifically the candidate genes associated with the regulation of Th2 cell responses on these three critical chromosomal regions, for which the evidence of association with and linkage to atopic phenotypes have been significant and consistent. We will continue to focus on the analysis of well-defined and previously studied populations. Systematic analysis of allelic polymorphisms within these candidate gene loci and their functional correlates will be pursued, with initial emphasis on recently identified sequence variants. Multiple statistics will be used to increase the power for linkage/association detection, including the Transmission Disequilibrium Test (TDT) and haplotype analysis. This proposal presents a continuing effort built upon our past accomplishments, with the aim being to identify susceptibility gene(s) regulating IgE responsiveness and/or asthma. It is anticipated that the accomplishment of these studies will greatly facilitate the efforts to uncover the genetic basis of IgE responsiveness and atopic diseases.